Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt stimulatory action on smooth muscle tissue. More specially, substance P is a pharmaceutically active neuropeptide that is produced in mammals (having originally been isolated from gut) and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in U.S. Pat. No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has recently been shown to be involved in the transmission of pain or migraine, as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, and in gastrointestinal disorders and diseases of GI tract, like ulcerative colitis and Crohn's diseases, etc.
It is reported that the tachykinin antagonists are useful for allergic conditions, immunoregulation, vasodilation, bronchospasm, reflex or neuronal control of the viscera and senile dementia of the Alzheimer type and for the treatment of emesis and sunburn.
In the recent past, some attempts to develop the tachykinin antagonist such as the one against substance P have been carried out for the purpose of the treatment of the above disorders or diseases.
WO 91/09844 and WO 93/0031 disclose a wide variety of azaheterocyclic compounds as tachykinin antagonists such as substance P antagonists. However, none of the azaheterocyclic compounds disclosed in these references has a carboxy group on the azaheterocyclic ring.
Under the circumstances, the present inventors have worked to prepare compounds useful as substance P antagonist, and after extensive research, have succeeded in synthesizing a series of compounds as will be disclosed in detail herein.
The purpose of the present invention is to provide the novel substituted azaheterocyclecarboxylic acid with substance P antagonistic activity. In addition, the purpose of the invention is also to provide the pharmaceutical composition, which includes the substituted azaheterocyclecarboxylic acid as an active ingredient, for treating of gastrointestinal disorders, central nervous system disorders, allergy, inflammatory diseases, asthma, pain, migraine or emesis in mammalia, especially human.